The present invention relates to new substituted heterocyclic compounds.
1. Description of the Prior Art
The new compounds have proved to be very powerful ligands for melatoninergic receptors.
From the prior art there are known benzoxathiin compounds used as fungicides (Hahn H. G. et al., J. Korean Chem. Soc., 1994, 38(10), pp. 776-81) or as lipogenesis inhibitors in mammals (U.S. Pat. No. 4,308,276).
Also known are a large number of (dihydro)chromene compounds as 5HT ligands for use in the treatment of hypertension, depression or anxiety (WO 9426703, DE 4135474), or dopaminergic receptor agonists (WO 9608489) for use in the treatment of cardiovascular diseases.
(Dihydro)benzodioxin compounds are furthermore described as anti-oxidants and inhibitors of lipid peroxidation (EP 624582), or for use in the treatment of liver diseases (J07242655 and J07242543), or as xcex1-adrenergic receptor blockers (Dewar G. H. et al., Eur. J. Med. Chem.xe2x80x94Chim. Ther., 1983, 18(3), pp 286-90).
2. Background of the Invention
In the last ten years, numerous studies have demonstrated the major role played by melatonin (5-methoxy-N-acetyltryptamine) in the control of the circadian rhythm and of endocrinal functions. In addition, melatonin receptors have been characterised and located.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp 321-341) and sleep disorders (Psychopharmacology, 1990, 100, pp 222-226), ligands for the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp 222-223) and also for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp 170-174). Those compounds have also exhibited activity in respect of certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University Press, 1988, pp 164-165), ovulation (Science 1987, 227, pp 714-720) and diabetes (Clinical Endocrinology, 1986, 24, pp 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp 443-446).
Compounds providing a means of acting on the melatoninergic system are accordingly excellent medicaments for the clinician for the treatment of pathologies associated with the melatoninergic system, especially those mentioned above.
The present invention relates more especially to compounds of formula (I): 
wherein
R1 represents a hydrogen atom, a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or an OR4 group (wherein R4 represents a hydrogen atom, a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted (C3-C8)cycloalkyl group or a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
R2 represents a hydrogen atom,
xe2x80x83or R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
X represents an oxygen atom, a sulphur atom, a C(H)q group (wherein q is equal to 0, 1 or 2), SO, SO2,
xe2x80x83or X represents a single bond when R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing two oxygen atoms,
Y represents an oxygen atom, a sulphur atom, a C(H)q group (wherein q is equal to 0, 1 or 2), SO or SO2,
it being understood that X and Y cannot simultaneously represent a C(H)q group (wherein q is equal to 0, 1 or 2),
R3 represents a hydrogen atom, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or a linear or branched (C1-C6)alkyl group,
n is equal to 0, 1, 2, 3, 4 or 5 when R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
xe2x80x83or n is equal to 1, 2, 3, 4 or 5 when R1 is as defined hereinabove and R2 represents a hydrogen atom,
it being possible for the xe2x80x94(CH2)nxe2x80x94 chain to be substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, OH, linear or branched (C1-C6)alkylcarbonyl and linear or branched (C1-C6)alkoxycarbonyl,
A represents
a NR5R6 group wherein
xe2x80x83R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
xe2x80x83R5 represents a 
xe2x80x83group wherein Z represents an oxygen atom
xe2x80x83or a sulphur atom, and R7 represents:
a hydrogen atom,
an R8 group which represents a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
or a NR8R9 group wherein R9 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group and R8 is as defined hereinabove,
or a 
xe2x80x83group wherein Z, R8 and R9 are as defined hereinabove,
the symbol 
xe2x80x83means that the bonds can be single or double, it being understood that two adjacent bonds cannot simultaneously be double and that the valency of the atoms is respected,
it being understood that:
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group optionally substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, cyano, nitro, amino, alkylamino, dialkylamino and trihaloalkyl,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9callynylxe2x80x9d means that the group is substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, amino, alkylamino and dialkylamino,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety is substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, oxo, amino, alkylamino and dialkylamino,
provided that:
when the compound of formula (I) is a 2,3-dihydro-1,4-benzodioxin compound (X and Y simultaneously represent an oxygen atom, R1, R2 and R3 simultaneously represent a hydrogen atom and the bonds 
xe2x80x83are single), the group xe2x80x94(CH2)nxe2x80x94A is other than the following groups:
CH2xe2x80x94NHCORa (wherein Ra represents an ethyl, 3,4,5-trimethoxyphenyl, 2,6-dimethoxyphenylethyl, phenylethyl, benzyl, phenyl, chloromethyl or trifluoromethyl group),
(CH2)2xe2x80x94NHCORb (wherein Rb represents a 2,3,4-trimethoxyphenyl group),
CH2xe2x80x94CONHRc (wherein Rc represents a methyl, ethyl, n-butyl, 2-hydroxypropyl or 3-methoxypropyl group),
(CH2)2xe2x80x94CONHRd (wherein Rd represents a methyl, 2-hydroxypropyl or 3-hydroxypropyl group),
when the compound of formula (I) is a chroman compound (X represents a CH2 group, Y represents an oxygen atom and R1, R2 and R3 are as defined hereinabove and the bonds 
xe2x80x83are single), the group xe2x80x94(CH2)nxe2x80x94A is other than the following groups:
CH2xe2x80x94NHCORe (wherein Re represents a cycloalkyl group) in the 2-position of the chroman group,
CH2xe2x80x94CONHRf (wherein Rf represents a benzyl or 1-phenyl-2-hydroxyethyl group) in the 4-position of the chroman group,
when A represents a NHCSNHR8 group and n is equal to 2, R8 cannot represent an aryl group,
when X represents a CH2 group, R1 is as defined hereinabove and R2 represents a hydrogen atom, A cannot represent a urea or thiourea group substituted by a substituted or unsubstituted phenyl group,
the compound of formula (I) cannot represent a thiochroman group (X represents a CH2 group, Y represents a sulphur atom, R1 is as defined hereinabove and R2 represents a hydrogen atom) substituted in the 3-position by a 
xe2x80x83chain wherein R8 and R9 are as defined hereinabove,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may mentioned by way of non-limiting examples hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc..
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting examples sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc..
An advantageous variant of the present invention relates to compounds of formula (I): 
wherein:
R1 represents a hydrogen atom, a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or an OR4 group (wherein R4 represents a hydrogen atom, a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted (C3-C8)-cycloalkyl group or a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched),
R2 represents a hydrogen atom,
xe2x80x83or R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
X represents an oxygen atom, a sulphur atom, a C(H)q group (wherein q is equal to 0, 1 or 2), SO or SO2,
Y represents an oxygen atom, a sulphur atom, a C(H)q group (wherein q is equal to 0, 1 or 2), SO or SO2,
it being understood that X and Y cannot simultaneously represent a C(H)q group (wherein q is equal to 0, 1 or 2),
R3 represents a hydrogen atom, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or a linear or branched (C1-C6)alkyl group,
n is equal to 0, 1, 2, 3, 4 or 5 when R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing one or two oxygen atoms,
xe2x80x83or n is equal to 1, 2, 3, 4 or 5 when R1 is as defined hereinabove and R2 represents a hydrogen atom,
xe2x80x83it being possible for the xe2x80x94(CH2)nxe2x80x94 chain to be substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, OH, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkylcarbonyl and linear or branched (C1-C6)alkoxycarbonyl,
A represents
a NR5R6 group wherein
xe2x80x83R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group
xe2x80x83R5 represents a 
xe2x80x83group wherein Z represents an
xe2x80x83oxygen atom or a sulphur atom, and R7represents:
a hydrogen atom,
an R8 group which represents a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
or a NR8R9 group wherein R9 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group and R8 is as defined hereinabove,
or a 
xe2x80x83group wherein Z, R8 and R9 are as defined hereinabove,
the symbol 
xe2x80x83means that the bonds can be single or double, it being understood that two adjacent bonds cannot simultaneously be double and that the valency of the atoms is respected,
it being understood that:
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group optionally substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, cyano, nitro, amino, alkylamino, dialkylamino and trihaloalkyl,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d means that the group is substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, amino, alkylamino and dialkylamino,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety is substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, oxo, amino, alkylamino and dialkylamino,
provided that:
when the compound of formula (I) is a 2,3-dihydro-1,4-benzodioxin compound (X and Y simultaneously represent an oxygen atom, R1, R2 and R3 simultaneously represent a hydrogen atom and the bonds 
xe2x80x83are single), the group xe2x80x94CH2)nxe2x80x94A is other than the following groups:
CH2xe2x80x94NHCORa (wherein Ra represents an ethyl, 3,4,5-trimethoxyphenyl, 2,6-dimethoxyphenylethyl, phenylethyl, benzyl, phenyl, chloromethyl or trifluoromethyl group),
(CH2)2xe2x80x94NHCORb (wherein Rb represents a 2,3,4-trimethoxyphenyl group),
CH2xe2x80x94CONHRc (wherein Rc represents a methyl, ethyl, n-butyl, 2-hydroxypropyl or 3-methoxypropyl group),
(CH2)2xe2x80x94CONHRd (wherein Rd represents a methyl, 2-hydroxypropyl or 3-hydroxypropyl group),
when the compound of formula (I) is a chroman compound (X represents a CH2 group, Y represents an oxygen atom and R1, R2 and R3 are as defined hereinabove and the bonds 
xe2x80x83are single), the group xe2x80x94(CH2)nxe2x80x94A is other than the following groups:
CH2xe2x80x94NHCORe (wherein Re represents a cycloalkyl group) in the 2-position of the chroman group,
CH2xe2x80x94CONHRf (wherein Rf represents a benzyl or 1-phenyl-2-hydroxyethyl group) in the 4-position of the chroman group,
when A represents a NHCSNHR8 group and n is equal to 2, R8 cannot represent an aryl group,
when X represents a CH2 group, R1 is as defined hereinabove and R2 represents a hydrogen atom, A cannot represent a urea or thiourea group substituted by a substituted or unsubstituted phenyl group,
the compound of formula (I) cannot represent a thiochroman group (X represents a CH2 group, Y represents a sulphur atom, R2 is as defined hereinabove and R2 represents a hydrogen atom) substituted in the 3-position by a 
xe2x80x83chain wherein R8 and R9 are as defined hereinabove,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Another advantageous variant of the present invention relates to compounds of formula (I): 
wherein:
R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them an aryl group, or a 6-membered ring containing two oxygen atoms,
X represents a single bond,
Y represents an oxygen atom, a sulphur atom, a C(H)q group (wherein q is equal to 0, 1 or 2), SO or SO2,
R3 represents a hydrogen atom, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or a linear or branched (C1-C6)alkyl group,
n is equal to 0, 1, 2, 3, 4 or 5, it being possible for the xe2x80x94(CH2)nxe2x80x94 chain to be substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, OH, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkylcarbonyl and linear or branched (C1-C6)alkoxycarbonyl,
A represents
a NR5R6 group wherein
xe2x80x83R6 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
xe2x80x83R5 represents a 
xe2x80x83group wherein Z represents an oxygen atom
xe2x80x83or a sulphur atom, and R7 represents:
a hydrogen atom,
an R8 group which represents a substituted or unsubstituted linear or branched (C1-C6)alkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl group, a substituted or unsubstituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a substituted or unsubstituted linear or branched (C2-C6)alkenyl group, a substituted or unsubstituted linear or branched (C2-C6)alkynyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
or a NR8R9 group wherein R9 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group and R8 is as defined hereinabove,
or a 
xe2x80x83group wherein Z, R8 and R9 are as defined hereinabove,
the symbol25
xe2x80x83means that the bonds can be single or double, it being understood that two adjacent bonds cannot simultaneously be double and that the valency of the atoms is respected,
it being understood that:
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group optionally substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, cyano, nitro, amino, alkylamino, dialkylamino and trihaloalkyl,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d means that the group is substituted by one or more halogen atoms or one or more identical or different groups selected from OH, linear or branched (C1-C6)alkoxy, amino, alkylamino and dialkylamino,
the term xe2x80x9csubstitutedxe2x80x9d used in respect of the terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety is substituted by one or more halogen atoms or one or more identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)-alkoxy, hydroxy, oxo, amino, alkylamino and dialkylamino,
provided that:
when A represents a NHCSNHR8 group and n is equal to 2, R8 cannot represent an aryl group,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
The preferred compounds of the invention are the compounds of formula (I) wherein:
R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them a phenyl or substituted phenyl group,
R1 and R2, located on two adjacent carbon atoms, form together with the carbon atoms that carry them a 6-membered ring containing one or two oxygen atoms,
R1 represents an OR4 group,
X represents a C(H)q group (wherein q is equal to 0, 1 or 2) and Y represents an oxygen or sulphur atom,
X and Y simultaneously represent an oxygen or sulphur atom,
X represents a single bond,
R3 represents a hydrogen atom,
R3 represents an aryl group,
A represents a group of formula NR5R6.
More especially, the present invention relates to dihydrobenzochromene, dihydrochromene, chromene and dihydro-6,7-ethylenedioxy-chromene compounds.
More especially still, the present invention relates to the compounds of formula (I) which are:
N-(9-methoxy-2,3-dihydro-1H-benzo[f]chromen-2-yl)acetamide
N-[2-(6-methoxy-3,4-dihydro-2H-chromenyl)ethyl]acetamide
N-[(6-methoxy-2H-3-chromenyl)methyl]butanamide.
The isomers and the addition salts, with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein R1, R2, R3, X and Y are as defined hereinabove, and nxe2x80x2 can have the values from 0 to 4,
which is subjected:
to a reducing agent to yield a compound of formula (III): 
xe2x80x83wherein R1, R2, R3, X, Y and nxe2x80x2 are as defined hereinabove,
which compounds of formula (III) can, moreover, be obtained
by reduction of a compound of formula (IV): 
xe2x80x83wherein R1, R2, R3, X, Y and n are as defined hereinabove,
or starting from a compound of formula (V): 
xe2x80x83wherein R1, R2, R3, X, Y and n are as defined hereinabove and Hal represents a halogen atom,
which is substituted by a phthalimide group and is then subjected to hydrazinolysis, with which compound of formula (III) there is condensed:
either an acyl chloride ClCOR8 or the corresponding acid anhydride (mixed or symmetrical) wherein R8 is as defined hereinabove,
to yield a compound of formula (I/a), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, R8, X, Y and n are as defined hereinabove,
which can be subjected to a thionisation agent, such as Lawesson""s reagent, to obtain a compound of formula (I/b), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, R8, X, Y and n are as defined hereinabove,
or a compound of formula (VI):
Zxe2x95x90Cxe2x95x90Nxe2x80x94R8xe2x80x83xe2x80x83(VI)
xe2x80x83wherein Z and R8 are as defined hereinabove,
in order to obtain a compound of formula (I/c), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, R8, X, Y, Z and n are as defined hereinabove,
the totality of the compounds of formulae (I/a), (I/b) and (I/c) constituting the compound of formula (I/d), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, X, Y and n are as defined hereinabove, and G represents a COR8, CSR8 or CZNHR8 group wherein Z and R8 are as defined hereinabove,
which can be alkylated in accordance with a conventional alkylation technique using a compound of formula (VII):
Alkxe2x80x94Wxe2x80x83xe2x80x83(VII)
xe2x80x83wherein Alk represents a linear or branched (C1-C6)alkyl group and W represents a leaving group, such as a halogen atom or a tosyl group,
or using a dialkyl sulphate,
to yield a compound of formula (I/e), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, X, Y, G, Alk and n are as defined hereinabove,
or to hydrolysis in an acidic or basic medium to yield a compound of formula (VIII): 
xe2x80x83wherein R1, R2, R3, X, Y and nxe2x80x2 are as defined hereinabove, which is subjected, after activation to the acid chloride form or in the presence of a coupling agent, to the action of an amine H2NR8 wherein R8 is as defined hereinabove,
to yield a compound of formula (I/f), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, R8, X, Y and nxe2x80x2 are as defined hereinabove,
which can be subjected to a thionisation agent, such as Lawesson""s reagent, to obtain a compound (I/g), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, R8, X, Y and nxe2x80x2 are as defined hereinabove,
the totality of the compounds (I/f) and (I/g) constituting the compound of formula (I/h): 
xe2x80x83wherein R1, R2, R3, R8, X, Y, Z and nxe2x80x2 are as defined hereinabove,
which can be alkylated in accordance with a conventional alkylation technique to yield a compound of formula (I/i): 
xe2x80x83wherein R1, R2, R3, R8, X, Y, Z, Alk and nxe2x80x2 are as defined hereinabove,
the compounds of formulae (I/a) to (I/i) constituting the totality of the compounds of formula(I), which can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
The compounds of formula (II) are obtained inter alia:
starting from compounds of formula (IX): 
xe2x80x83wherein R1 and R2 are as defined hereinabove and Xxe2x80x2 represents a sulphur atom or an oxygen atom,
which is condensed with acrylonitrile, to yield a compound of formula (II/a), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2 and Xxe2x80x2 are as defined hereinabove,
which is subjected to reduction to obtain a compound of formula (II/b), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2 and Xxe2x80x2 are as defined hereinabove,
starting from compounds of formula (X): 
xe2x80x83wherein R1, R2 and Xxe2x80x2 are as defined hereinabove,
which is subjected to a Wittig reaction followed by catalytic reduction to obtain a compound of formula (II/c), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2 and Xxe2x80x2 are as defined hereinabove and p is equal to 0, 1, 2, 3 or 4,
starting from compounds of formula (XI): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove,
with which there is condensed:
chloroacrylonitrile to obtain a compound of formula (II/d), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove,
which can be dibrominated and then treated with sodium iodide to yield a compound of formula (II/e), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove,
or ethyl 2,3-dibromopropionate to yield a compound of formula (XII): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove,
which can be dibrominated and then treated with sodium iodide to yield a compound of formula (XIII): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove,
the totality of the compounds (XII) and (XIII) constituting the compound of formula (XIV): 
xe2x80x83wherein R1, R2, X and Y are as defined hereinabove and the symbol 
xe2x80x83means that the bond can be single or double,
which compound (XIV) is subjected to lithiation followed by condensation with the desired electrophile in order to yield a compound of formula (XV): 
xe2x80x83wherein R1, R2, R3, X, Y and the symbol 
xe2x80x83are as defined hereinabove,
which may be, in succession, reduced to the corresponding alcohol, oxidised to the aldehyde and subjected to a Wittig reaction to yield a compound of formula (XVI): 
xe2x80x83wherein R1, R2, R3, X, Y and the symbol 
xe2x80x83are as defined hereinabove and q is equal to 0, 1, 2 or 3,
which is reduced catalytically to yield a compound of formula (Il/f), which is a particular case of the compounds of formula (II): 
xe2x80x83wherein R1, R2, R3, X, Y, nxe2x80x2 and the symbol 
xe2x80x83are as defined hereinabove.
The invention relates also to a process for the preparation of compounds of formula (I) wherein X represents a single bond, characterised in that a compound of formula (XVII): 
wherein Y, R1 and R2 are as defined hereinabove and Hal represents a halogen atom,
is condensed with a compound of formula (XVIII):
R3xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)nxe2x80x94Axe2x80x83xe2x80x83(XVIII)
wherein R3, n and A are as defined hereinabove, to obtain a compound of formula (I/j), which is a particular case of the compounds of formula (I): 
xe2x80x83wherein R1, R2, R3, Y, n and A are as defined hereinabove,
which compounds of formula (I/j) can be purified in accordance with a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base and, optionally, are separated into their isomers in accordance with a conventional separation technique.
The compounds of the invention and the pharmaceutical compositions containing them have proved to be useful in the treatment of disorders of the melatoninergic system.
A pharmacological study of the compounds of the invention has in fact shown them to be non-toxic, to have a very high selective affinity for melatonin receptors and to possess important activities in respect of the central nervous system and, in particular, therapeutic properties in relation to sleep disorders, anxiolytic, antipsychotic and analgesic properties and activity on the microcirculation, enabling it to be established that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, insomnia and fatigue resulting from jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and also cerebral circulation disorders. In another field of activity, it appears that, in treatment, the products of the invention have ovulation-inhibiting properties and immunomodulating properties and are able to be used in the treatment of cancers. The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue resulting from jet lag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising products of formula (I) in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, percutaneous, transcutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets, dragees, sublingual tablets, sachets, paquets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possible associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in 1 or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
1 g of 2,3-dihydro-1,4-benzodioxin-6-yl acetate (5.149 mmol) is dissolved in a solution of methanol (7.5 ml) and, under an argon atmosphere, the mixture is made basic, dropwise, with a 10% sodium hydroxide solution. The mixture is stirred at ambient temperature for 4 hours. At the end of the reaction, the methanol is evaporated and the reaction medium is acidified (to pH=1) with a 2N HCl solution and then washed with ethyl acetate. After extraction, drying over MgSO4 is carried out and the product is concentrated in vacuo. Purification on a silica column allows an oil to be obtained (eluant: PE/AcOEt 8/2 then 7/3).
3 g (18.05 mmol) of the alcohol obtained in Step A are dissolved in 10 ml of DMF in a flask. 2 eq. of NaH (60% in oil) are added slowly and allowed to act for 30 minutes under an inert atmosphere. 2 eq. of iodomethane are then added. The mixture is stirred for 2 hours; the DMF is then evaporated. Washing with ethyl acetate and with water is carried out and the two phases are separated. The combined organic phases are dried over MgSO4 and the solvent is evaporated. The oil obtained is purified on a silica column (eluant: PE/AcOEt 8/2), which allows the pure title product to be obtained.
3.3 eq. of dry DMF are placed in a three-necked flask and then, using a dropping funnel, 1.3 eq. of phosphorus oxychloride are added at 0xc2x0 C. After returning to ambient temperature, the compound obtained in Step B (4 g: 20.59 mmol) is dissolved in 6.5 ml of DMF and then added to the previous solution. Heating is carried out for 2 hours at 110xc2x0 C. After cooling, the mixture is hydrolysed with water and extracted with dichloromethane.
The organic phases are dried over MgSO4. After evaporation of the solvent, the oil is chromatographed on a silica column (eluant: PE/AcOEt 7/3). Melting point: 130-131xc2x0 C.
4 eq. of AlCl3 are suspended in 10 ml of anhydrous CH2Cl2. Under an inert atmosphere, 100 mg (5.55 mmol) of the compound obtained in Step C, dissolved in 10 ml of anhydrous CH2Cl2, are added to that mixture and allowed to act for 2 hours at ambient temperature. The mixture is hydrolysed with an ice-cold 2N HCl solution; the solution is then extracted with CH2Cl2 and dried over MgSO4. After evaporation of the solvent, purification on a silica column (eluant: PE/AcOEt 7/3) is carried out and the pure product is isolated.
Melting point: 114-115xc2x0 C.
Methylation of 2,7-dihydroxynaphthalene (10 g: 62.43 mmol) is carried out in acetone (100 ml) in the presence of dimethyl sulphate (12.06 ml:127 mmol:2.03 eq.) and dry potassium carbon-ate (42.3 g:306 mmol:4.9 eq.). The temperature of the reaction medium is 56xc2x0 C. for 6 hours and then 40xc2x0 C for 12 hours. Hydrolysis (7.4 ml of water) requires 2 hours of stirring at ambient temperature. After filtering off the salts over Celite and concentrating the remaining filtrate, extraction with dichloromethane yields an organic phase, which, after evaporation, has the appearance of a beige solid. The latter is rendered colourless using active carbon and then recrystallised from a PE/CH2Cl2 mixture.
Melting point: 138xc2x0 C.
Titanium tetrachloride (4.09 ml:37.5 mmol:1.4 eq.) and xcex1xcex1-dichloromethyl methyl ether (3.6 ml:37.5 mmol:1.5 eq.), previously dissolved in 14 ml of dichloromethane, are injected in succession into a solution of the compound obtained in Step A (5 g: 26.3 mmol) in anhydrous dichloromethane (50 ml). After those operations have been carried out at 0xc2x0 C., the temperature is gradually returned to 25xc2x0 C. and that temperature is then maintained for 5 hours. The reaction mixture is then slowly poured onto ice, and a 3N hydrochloric acid solution (103 ml) is subsequently added with caution. After hydrolysis of the complex, the product is extracted with dichloromethane, washed with water and then with a saturated solution of sodium hydrogen carbonate. The dry residue recovered after concentration is washed with diethyl ether, thereby allowing isolation of the pure aldehyde.
Melting point: 94xc2x0 C.
After the dimethoxylated product obtained in Step B (2 g: 9.25 mmol) has been dissolved in anhydrous dichloromethane, 97% BBr3Me2S complex (2.98 g: 9.25 mmol 1 eq.) is introduced at ambient temperature. After 35 minutes of stirring, hydrolysis is carried out with a saturated solution of sodium hydrogen carbonate (pH=8). The product is extracted with dichloromethane and then purified on a silica column AcOEt/PE (3/7).
Melting point: 126xc2x0 C.
Under an anhydrous atmosphere, the aldehyde obtained in Step C (2 g: 9.9 mmol) is partially solubilised in acrylonitrile (6.5 ml:49.4 mmol:10 eq.). The solution becomes clear after the addition of 1,4-diazabicyclo[2.2.2]octane (227 mg:2.47 mmol:0.25 eq.) and becomes a red colour when heated at reflux for a period of 18 hours. The reaction medium is then diluted with ethyl acetate and washed in succession with a 1N sodium hydroxide solution (20 ml) and then a 1N hydrochloric acid solution (20 ml). The concentrated organic phases are purified on a flash silica column eluted with an AcOEt/PE mixture (0.1/1).
Melting point: 134xc2x0 C.
1.45 g (15.5 mmol) of 2-chloroacrylonitrile and 6 g (43.5 mmol) of dry potassium carbonate are added in succession to 6.6 g (60 mmol) of catechol dissolved in 80 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the mixture is then heated to boiling. After 18 hours at reflux under argon, the reaction mixture is cooled and then filtered over Celite. After evaporation of the solvent, the residue is taken up in a water/ethyl acetate mixture (50:50) and then the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is evaporated under reduced pressure. The title nitrile is obtained pure in the form of a white solid after purification on a silica column (eluant: AcOEt/PE 30/70).
Melting point: 58xc2x0 C.
26 g (100 mmol) of ethyl 2,3-dibromopropionate and 36.4 g (264 mmol) of anhydrous potassium carbonate are added to 40 g (181 mmol) of catechol dissolved in 200 ml of anhydrous acetone. The operation is repeated 4 times within one hour; the reaction mixture is then heated to boiling. After 18 hours at reflux under argon, the mixture is cooled and then filtered over Celite. After concentration of the filtrate in vacuo, the residue is hydrolysed and then the aqueous phase is extracted with ether. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The title ester is obtained pure by distillation under reduced pressure (15 mm Hg; b.p.=155xc2x0 C.).
6 g (28.88 mmol) of the 2,3-dihydrobenzodioxin ester obtained in Preparation 4 and 11.25 g (63.38 mmol) of N-bromosuccinimide are added to 100 ml of anhydrous carbon tetrachloride containing a spatula tip of AIBN; the mixture is then heated at reflux under an inert atmosphere for 4 hours. The succinimide formed is then filtered off; the solvent is then evaporated under reduced pressure to yield the dibrominated ester of the title in the form of an orange solid.
Melting point: 92xc2x0 C.
12 g (32.78 mmol) of the dibrominated compound obtained in Step A are dissolved in 60 ml of anhydrous acetone; 18 g (120 mmol) of sodium iodide are then added to the solution. After 4 hours of stirring at ambient temperature and under argon, the solvent is evaporated in vacuo and the residue is then taken up in water. The aqueous phase is then extracted with ethyl acetate; the organic phase is then rendered colourless using a saturated solution of sodium thiosulphate. After drying over magnesium sulphate and filtration, the solvent is evaporated under reduced pressure. The residue obtained is purified on a silica column (eluant: AcOEt/PE 30/70) to yield the title ester in the form of a chestnut-brown solid.
Melting point: 42xc2x0 C.
9 g (115.4 mmol) of acetyl chloride are added to a solution of 16 g (77 mmol) of the ester obtained in Preparation 4 in 120 ml of anhydrous carbon disulphide. The temperature is lowered to 0xc2x0 C.; 25.70 g (192.8 mmol) of aluminium chloride are then added very slowly to the reaction medium. After 4 hours of stirring under an inert atmosphere, the mixture is hydrolysed with an ice-cold 2N hydrochloric acid solution and then extracted with dichloromethane. The organic phase is then washed with a saturated solution of sodium hydrogen carbonate and then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the two title esters are obtained in the form of a yellow oil after passage over a silica column (eluant: Et2O/PE: 40/60).
16 g (75.4 mmol) of the mixture of the two esters obtained in Step A are dissolved in 150 ml of an ethanol/water mixture (3:1). After addition of 50 ml of a 28% solution of ammonia, the reaction medium is stirred for 3 days at ambient temperature. The title amide precipitates from the medium whereas the isomer acylated in the 6-position remains in solution. After filtering off the precipitate and washing several times with ethanol, the solid obtained is recrystallised twice or three times from a water/ethanol mixture (70/30).
Melting point: 220xc2x0 C.
150 ml of ethanol are saturated with hydrochloric acid; 6 g (27.12 mmol) of the amide obtained in Step B are then added to the medium. After 18 hours of reflux, the mixture is cooled and then filtered. The filtrate is concentrated in vacuo and the residue is taken up in water; the aqueous phase is then neutralised with solid sodium hydrogen carbonate. After extraction with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and then concentrated in vacuo. The title ester is obtained in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 30/70).
Melting point: 57xc2x0 C.
4 g (16 mmol) of the ester obtained in Step C are dissolved in 60 ml of anhydrous dichloromethane; 6.1 g (35.4 mmol) of meta-chloroperbenzoic acid are then added to the medium. After 18 hours of reflux under an inert atmosphere, the mixture is cooled and then hydrolysed with ice-cold water. The aqueous phase is extracted with dichloromethane; the organic phase is then washed several times with a saturated solution of sodium hydrogen carbonate. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant: AcOEt/PE: 30/70) to yield the title ester in the form of a syrup.
A solution of 6 g (44.1 mmol) of 2,3-dihydro-1,4-benzodioxin and 18.8 g (105.6 mmol) of N-bromosuccinimide in 80 ml of anhydrous carbon tetrachloride is heated at reflux under an inert atmosphere after having added a spatula tip of AIBN. After 2 hours, the succinimide formed is filtered off; the solvent is then evaporated in vacuo. The crude dibrominated product is then taken up in 90 ml of anhydrous ether; 9.9 g (88.2 mmol) of potassium tert-butylate are then slowly added to that solution. After 8 hours of stirring under argon and at ambient temperature, the salts are filtered off over Celite; the solvent is then evaporated in vacuo. The title brominated product is obtained pure in the form of a clear oil after passage over a silica column (eluant: PE).
3.73 g (17.5 mmol) of the compound obtained in Step A are dissolved in 90 ml of anhydrous tetrahydrofuran; the mixture is then cooled to xe2x88x9278xc2x0 C. 16.4 ml (26.25 mmol) of n-butyllithium (1.6 M/hexane) are then slowly added to the solution; the reaction mixture is then stirred for 2 hours under argon at the same temperature. 2.2 ml (17.5 mmol) of boron trifluoride etherate and an excess of ethylene oxide are added in succession to the solution. After 30 minutes of stirring at xe2x88x9278xc2x0 C., the reaction mixture is hydrolysed with a saturated ammonium chloride solution; the aqueous phase is then extracted with ethyl acetate. The organic phase dried over magnesium sulphate and then filtered, is concentrated in vacuo. The title alcohol is obtained pure in the form of a clear oil after passage over a silica column (eluant: AcOEt/PE: 20/80).
2.27 g (12.77 mmol) of the alcohol obtained in Step B are dissolved in 50 ml of anhydrous dichloromethane. 3.65 g (18.35 mmol) of tosyl chloride and 5.3 ml (38.1 mmol) of triethylamine are added in succession to the medium; the solution is then stirred for 18 hours at ambient temperature and under an inert atmosphere. After evaporation of the solvent in vacuo, the title tosylate is obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 15/85) in a quantitative yield.
Melting point: 103-105xc2x0 C.
1.33 g (4 mmol) of the tosylate obtained in Step C are dissolved in 50 ml of anhydrous acetone. 1.2 g (8 mmol) of sodium iodide are then added to the medium; the solution is then heated at reflux for 3 hours under argon. After cooling of the mixture, the solvent is evaporated in vacuo; the residue is then taken up in water. The aqueous phase is extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The iodinated compound is obtained pure in the form of a clear oil after passage over a silica column (eluant: AcOEt/PE: 20/80).
1 g (3.47 mmol) of the iodinated compound obtained in Step D and 0.964 g (5.2 mmol) of potassium phthalimide are dissolved in 20 ml of anhydrous N,N-dimethylformamide; the reaction mixture is then heated at 60xc2x0 C. for 22 hours under argon. After cooling of the mixture, the solvent is evaporated in vacuo; the residue is then taken up in ethyl acetate. After washing with water and extraction of the aqueous phase with ethyl acetate, the organic phases are dried over magnesium sulphate. The solvent is then evaporated in vacuo; the title phthalimide is then obtained pure in the form of a white solid after passage over a silica column (eluant: AcOEt/PE: 30/70).
Melting point: 122-123xc2x0 C.
0.837 g (2.37 mmol) of the phthalimide obtained in Step E and 0.358 g (7.16 mmol) of hydrazine monohydrate are dissolved in 20 ml of tetrahydrofuran; the mixture is then heated at reflux for 5 hours. After filtering off the solid, the filtrate is concentrated in vacuo; the residue is then taken up in dichloromethane and dried over magnesium sulphate. The filtered organic phase is concentrated in vacuo to yield the amine in the form of a yellow oil.
6 g (22.6 mmol) of the ester obtained in Preparation 6 are dissolved in 120 ml of anhydrous carbon tetrachloride; 8.8 g (49.6 mmol) of N-bromosuccinimide are then added to the medium. After having added a spatula tip of AIBN, the reaction mixture is heated at reflux for 6 hours under an inert atmosphere. The succinimide formed is then filtered off; the filtrate is then concentrated in vacuo to yield the dibrominated product quantitatively. 10 g (23.6 mmol) of the dibrominated product and 14.4 g (82.6 mmol) of sodium iodide, dissolved in 170 ml of anhydrous acetone, are stirred for 4 hours under an inert atmosphere. After evaporation of the solvent in vacuo, the residue is taken up in water; the aqueous phase is then extracted with ethyl acetate. The organic phase is rendered colourless using a saturated solution of sodium thiosulphate. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the residue obtained is purified on a silica column (eluant: AcOEt/PE: 30/70) to yield the title ester in the form of a white solid.
Melting point: 66xc2x0 C.
0.84 g (3.78 mmol) of the ester obtained in Step A is dissolved in 20 ml of anhydrous ethanol; the medium is then adjusted to a basic pH using a molar solution of sodium ethanolate (0.5 ml). After 18 hours of stirring under an inert atmosphere and at ambient temperature, the reaction mixture is neutralised with DOWEX X-8 resin (acid form). The solid is then filtered off; the filtrate is then concentrated in vacuo. The residue obtained is purified on a silica column (eluant: AcOEt/PE: 50150) to yield the title compound in the form of a white solid.
Melting point: 160xc2x0 C.
2.8 g (12.75 mmol) of the ester obtained in Step B are dissolved in 30 ml of anhydrous N,N-dimethylformamide. 0.61 g (16 mmol) of sodium hydride is then added slowly to the reaction mixture previously cooled to 0xc2x0 C. After 30 minutes of stirring under argon and at 0xc2x0 C., 2.28 g (16 mmol) of iodomethane are added to the reaction medium. After 4 hours of stirring at ambient temperature, the solvent is evaporated in vacuo; the residue obtained is then taken up in water and then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The title ester is obtained pure in the form of a white solid after passage over a silica column (eluant: ethyl acetate/petroleum ether: 30/70).
Melting point: 64xc2x0 C.
4 g (19.4 mmol) of the ester obtained in Preparation 5 are dissolved in 70 ml of ethanol; the solution is then cooled to 0xc2x0 C. 30 ml of a 15% sodium hydroxide solution are slowly added to the medium. After 30 minutes of stirring at 0xc2x0 C., the solvent is evaporated in vacuo; the residue is then acidified with a hydrochloric acid solution (1N). The aqueous phase is extracted with ethyl acetate; the organic phase is then dried over magnesium sulphate. Evaporation of the solvent in vacuo yields the title acid in the form of a brown solid.
Melting point: 183-184xc2x0 C.
A solution of 32.5 ml (65 mmol) of lithium diisopropylamide (2M/heptane) in 40 ml of anhydrous THF is cooled to xe2x88x9278xc2x0 C. 3.3 g (18.5 mmol) of the acid obtained in Step A, dissolved in 20 ml of anhydrous THF, are slowly added to the medium. After 5 hours of stirring at xe2x88x9278xc2x0 C., 19.6 ml (65 mmol) of tributyltin chloride are added to the medium. After 1 hour, hydrolysis with a saturated solution of ammonium chloride is carried out; the aqueous phase is then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The stannylated acid so formed is dissolved in 40 ml of N,N-dimethylacetamide; 14.31 g (170 mmol) of sodium hydrogen carbonate and also 5.31 ml (85 mmol) of iodomethane are then added to that solution. The reaction medium is then stirred for 40 hours under argon and with protection from light. After evaporation of the solvent in vacuo, the residue is taken up in water; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The stannylated ester of the title is then purified by passage over a silica column (eluant: AcOEt/CH2Cl2/PE:2.5/2.5/95).
9.4 g (19.3 mmol) of the stannylated ester obtained in Step B are dissolved in 70 ml of 1,4-dioxane; 0.74 g (0.69 mmol) of tetrakis(triphenylphosphine)palladium, 5.9 g (28.9 mmol) o iodobenzene and 0.26 g (1.38 mmol) of cuprous iodide are then added in succession to the medium. The reaction mixture is then heated at reflux for 2 hours under an inert atmosphere. After filtering off the remaining catalyst over Celite, the filtrate is concentrated under reduced pressure. The residue obtained is purified on a silica column (eluant: AcOEt/CH2Cl2/PE: 2.5/2.5/95) to yield the title ester in the form of a brown solid in an overall yield of 67% for the 3 final Steps.
Melting point: 73xc2x0 C.
3 g (12.7 mmol) of the ester obtained in Preparation 8 are dissolved in 40 ml of a 3:1 mixture of ethanol/tetrahydrofuran; the solution is then cooled to 0xc2x0 C. The medium is then made alkaline with an 8% sodium hydroxide solution; stirring is then maintained for 30 minutes more at 0xc2x0 C. After evaporation of the solvents under reduced pressure, the aqueous phase is extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo to yield the title acid in the form of a white solid.
Melting point: 197xc2x0 C.
The acid obtained in Step A is stannylated according to the same procedure as in Step B of Preparation 9. 3.67 g (7.40 mmol) of the resulting crude stannylated acid are dissolved in 25 ml of N,N-dimethylacetamide; 2.3 ml (37 mmol) of iodomethane and 6.21 g (74 mmol) of sodium hydrogen carbonate are then added in succession to the medium. After 4 days of stirring at ambient temperature with protection from light, the solvent is evaporated under reduced pressure; the residue obtained is then taken up in water. The aqueous phase is extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on silica gel (eluant: AcOEt/PE: 2.5/97.5) yields the title ester in the form of a clear oil.
0.244 g (0.22 mmol) of tetrakis(triphenylphosphine)palladium and 0.084 g (0.44 mmol) of cuprous iodide are added to a solution of 2.15 g (4.36 mmol) of the ester obtained in Step B and of 1.33 g (6.54 mmol) of iodobenzene in 25 ml of 1,4-dioxane. The reaction mixture is then heated at reflux under an inert atmosphere for 2 hours and then allowed to cool. After filtering off the remaining catalyst over Celite, the solvent is evaporated in vacuo. The residue obtained is purified on a silica column (eluant: AcOEt/PE: 15/85) to yield the title ester in the form of an oil which crystallises slowly.
Melting point: 82-83xc2x0 C.
A solution of 0.61 g (4 mmol) of 2-hydroxy-5-methoxybenzaldehyde and 0.112 g (1 mmol) of 1,4-diazabicyclo[2.2.2]octane in 18 ml of acrylonitrile is heated at reflux for 24 hours under argon. After cooling, the medium is diluted with chloroform and then washed with a saturated solution of sodium hydrogen carbonate. The organic phase is then acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with chloroform. The organic phases, dried over magnesium sulphate and then filtered, are concentrated under reduced pressure. The title nitrile is obtained pure in the form of a yellow solid after passage over a silica column (eluant: AcOEt/PE: 25/75).
Melting point: 70-71 xc2x0 C.
3.18 g (17 mmol) of nitrile obtained in Preparation 11 are added to 50 ml of a 10% sodium hydroxide solution; the reaction mixture is then heated at reflux for 4 hours. After cooling of the mixture, the solvent is evaporated in vacuo; the residue obtained is then acidified with a hydrochloric acid solution (1N). The aqueous phase is then extracted with ethyl acetate; the organic phase is then dried over magnesium sulphate. Evaporation of the solvent under reduced pressure yields the pure title acid in the form of a yellow solid.
Melting point: 199xc2x0 C.
A solution of 2.5 g (12.13 mmol) of the acid obtained in Step A in 30 ml of anhydrous tetrahydrofuran is cooled to xe2x88x9216xc2x0 C.; 2.5 ml (18.2 mmol) of triethylamine are then added dropwise to the medium. After 10 minutes of stirring, 1.98 g (18.2 mmol) of ethyl chloroformate are slowly added to the reaction mixture. The solution is stirred under argon for 3 hours, the salts are filtered off and then the filtrate is cooled to xe2x88x9216xc2x0 C. 1.84 g (48.5 mmol) of sodium borohydride are added to the medium all at once; 10 ml of methanol are then added very slowly to the solution. After 2 hours of stirring at xe2x88x9216xc2x0 C., the reaction mixture is hydrolysed with a saturated solution of ammonium chloride; the aqueous phase is then extracted with ethyl acetate. The organic phase, dried over magnesium sulphate and then filtered, is concentrated under reduced pressure. The allyl alcohol of the title is obtained pure in the form of a yellow oil after passage over a silica column (eluant: AcOEt/PE: 30/70 then 50/50).
A solution of 7.5 g (31.8 mmol) of the compound obtained in Step A of Preparation 1, protected at the dihydropyran, in 70 ml of anhydrous tetrahydrofuran is cooled to xe2x88x9250xc2x0 C.; 60 ml (95.4 mmol) of a solution of n-butyllithium (1.6 M/hexane) are then slowly added to the medium. After 2 hours of stirring at that temperature, 10.7 ml (159 mmol) of DMF are slowly added to the solution; stirring is then maintained for 1 hour more at xe2x88x9250xc2x0 C. After returning to ambient temperature, the reaction mixture is hydrolysed with water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. The residue obtained is passed over a silica column (eluant: ethyl acetate/petroleum ether: 10/90 then 25/75) to yield the title aldehyde in the form of yellow crystals.
Melting point: 84xc2x0 C.
5 g (18.9 mmol) of the aldehyde obtained in Step A are dissolved in 50 ml of aqueous methanol (90%); 10 ml of a 5% aqueous solution of oxalic acid are then added to the medium. After 3 hours of stirring at ambient temperature, the solvent is evaporated in vacuo; the residue is then taken up in dichloromethane and then washed with a saturated solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography on a silica column (eluant: ethyl acetate/petroleum ether: 10/90) allows the title compound to be obtained in the form of white crystals.
Melting point: 62-63xc2x0 C.
3 g (16.6 mmol) of the compound obtained in Step B and 1.4 g (25 mmol) of acrolein are added to a suspension of 3.48 g (25 mmol) of potassium carbonate in 40 ml of 1,4-dioxane; the medium is then heated at reflux under argon for 3 hours. After cooling and filtering off the salts, the solvent is evaporated in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography on a silica column (eluant: ethyl acetate/petroleum ether 10/90) allows the title compound to be obtained in the form of a yellow solid.
Melting point: 124-125xc2x0 C.
2.18 g (10 mmol) of the aldehyde obtained in Step C are dissolved in 25 ml of anhydrous ethanol and then 0.38 g (10 mmol) of sodium borohydride is added to the medium. After 15 minutes of stirring, the solvent is evaporated in vacuo; the residue obtained is then acidified with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then dried over magnesium sulphate and then concentrated under reduced pressure. The crude product is passed over a silica column (eluant: petroleum ether/ethyl acetate: 70/30 then 50150) to yield the title alcohol in the form of a clear syrup.
3.83 g (9.09 mmol) of dibromotriphenylphosphorane are added to a solution of 2 g (9.09 mmol) of the alcohol obtained in Step D in 25 mmol of acetonitrile. After 15 min of stirring under argon, the solvent is evaporated in vacuo; the residue obtained is then taken up in 50 ml of a mixture of ether/hexane (1/1). The precipitate formed is filtered off and then washed several times with the same mixture. The organic phase is concentrated under reduced pressure to yield the brominated product of the title in the form of a chestnut-brown syrup.
2.36 g (12.75 mmol) of potassium phthalimide and also 0.166 g (1 mmol) of potassium iodide are added to a solution of 2.54 g (8.5 mmol) of the brominated compound obtained in Step E in 20 ml of anhydrous N,N-dimethylformamide; the medium is then stirred under argon for 10 hours. The solvent is evaporated in vacuo; the residue obtained is then taken up in water and extracted with dichloromethane. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. Chromatography on a silica column (eluant: ethyl acetate/petroleum ether 10/90) yields the title phthalimide in the form of a white solid.
Melting point: 137xc2x0 C.
1 g (3.02 mmol) of the phthalimide obtained in Step E is dissolved in 25 ml of tetrahydrofuran. After adding 0.6 g (12 mmol) of hydrazine hydrate, the medium is heated at reflux for 4 hours and then allowed to cool. The solid formed is filtered off, the filtrate is then concentrated in vacuo to yield the title amine in the form of a yellow oil.
The procedure is as in Step A of Example 12, starting from 7-methoxy-1,4-dihydro-2-naphthol.
The procedure is as in Steps B and C of Example 12.
In an anhydrous medium, the ketone obtained in Preparation 14 (500 mg, 2.19 mmol), diethylcyanophosphonate (2 eq; 4.38 mmol, 715 xcexcl) and also a 0.5M solution of lithium cyanide in DMF (3 eq; 6.57 mmol, 13.15 ml) are mixed in 20 ml of THF. After 30 minutes of stirring, the reaction mixture is hydrolysed and then extracted with AcOEt. In parallel, a solution of samarium iodide is prepared. The samarium (4.5 eq; 9.86 mmol; 1.48 g) is suspended in 10 ml of THF and then diiodoethane (3 eq; 6.57 mmol; 1.85 g), diluted in 10 ml of TEF, is added dropwise. When the samarium iodide solution has become blue, the previously formed complex is dissolved in 5 ml of THF and 0.21 ml of tert-butanol and then added. The solution is stirred for 12 hours at ambient temperature. The reaction mixture is hydrolysed with a 10% HCl solution. After extraction with AcOEt, the organic phase is washed with a 10% solution of Na2S2O3 and then twice with a saturated solution of NaHCO3. The residue obtained is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of an oil.
In an anhydrous medium, diethyl cyanomethylphosphonate (3 eq; 17.1 mmol; 2.76 ml) is added slowly to a suspension of 50% sodium hydride (3 eq; 17.1 mmol; 820 mg) in 50 ml of THF, at 0xc2x0 C. The reaction medium is stirred for 10 minutes at 0xc2x0 C. and then cooled to xe2x88x9278xc2x0 C. The ketone obtained in Preparation 14 (1.3 g; 5.7 mmol), dissolved in 15 ml of THF, is added. The temperature is then slowly returned to 20-25xc2x0 C. over 2 hours 30. After removal of the solvent, the compound is extracted with AcOEt. The organic phase is washed with a large amount of a saturated solution of NaCl and then concentrated under reduced pressure. The desired product is obtained in the form of a solid.
Melting point 61-63xc2x0 C.
The unsaturated compound obtained in Step A (1.775 eq; 7.07 mmol.), solubilised in 50 ml of ethanol and a few drops of THF, is introduced into a Parr reactor. 10% palladium-on-carbon (266 mg; 15% by weight) is then added. The mixture is left under hydrogen pressure of 45 psi, with stirring, for 18 hours. After filtration over Celite, the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (eluant: PE/AcOEt to (9/1)). The desired product is obtained in the form of a solid. Melting point: 122-123xc2x0 C.
The title product is obtained by condensation in sodium hydride of acetophenone with ethyl 5-methoxy-2-(methoxymethoxy)benzoate, and then the action of HCl in ethanol.